Clot formation is an important biological reaction that forms hemostatic plugs to stop bleeding in normal processes. However, abnormal clot formation is thought to be responsible for ischemic diseases that are considered to be a major cause of death in Japan and western countries. Many diseases are caused by pathological blood clots, and those reported include, for example, ischemic heart diseases (myocardial infarction, angina), intraatrial thrombus, pulmonary embolism, deep venous thrombosis, disseminated intravascular coagulation, ischemic cerebral diseases (cerebral infarction, cerebral bleeding) and arteriosclerosis. Currently, a number of medicaments are being used for these pathological blood clots. As representative medicaments, there can be mentioned anti-platelet agents, inhibitors of blood coagulation factors, vitamin K inhibitors and fibrinolytic agents.
The activation of the fibrinolytic system is triggered by the activation of plasminogen by plasminogen activators t-PA and urokinase to plasmin, and the formed plasmin decomposes fibrin, a constituent of blood clots, to allow thrombolysis to proceed. Among them, a physiological control factor for plasminogen activator is PAI-1 that is released from vascular endothelial cells or the activated platelets. PAI-1 is composed of 379 amino acids, and is a glycoprotein with a molecular weight of about 50 kDa having no intramolecular S—S bonds. PAI-1 binds to the enzymatic active center of t-PA at a molar ratio of 1:1, and inhibits the t-PA activity. Under normal conditions, fibrinolytic control factors keep equilibrium with each other causing no bleeding or clotting to attain smooth blood flow in the blood vessel. However, it is thought that in pathological thrombosis and vascular endothelial cells, t-PA production is reduced whereas PAI-1 secretion is increased. Thus, it is thought that by inhibiting PAI-1 that is increased in pathological thrombosis, a therapeutic effect may be exhibited.
On the other hand, pathological conditions in which fibrin is involved is not limited to thrombosis, and it is known that fibrin clots are massively formed in tissue fibrinosis as well. Though fibrinosis is a pathological condition that is observed in various organs including the lung, the kidney, the liver, the skin, cerebral nerves, blood vessels and the like, the pathological causes have not been elucidated much less the therapeutic methods. There are reports on bleomycin-induced pulmonary fibrosis which is an animal model of fibrinosis. It has been reported that in PAI-1 knockout mice, the enhancement in the amount of hydroxyproline that is an index of fibrinolysis is inhibited, and in mice over-expressing PAI-1 the production of hydroxyproline is increased compared to the control (J. Clin. Invest. 97, 232 (1996)). It is also reported that by administering uPA that is increased by inhibiting PAI-1, the formed fibrins can be dissolved (Clin. Invest. Med., 17: 69-76 (1994)). These suggest that the inhibition of PAI-1 may lead to a therapeutic effect for fibrinolysis.
So far, compounds that inhibit PAI-1 are known (Kokai (Japanese Unexamined Patent Publication) No. 7-149642, Kokai No. 7-149643, Kokai No. 7-165573, Kokai No. 7-165574, Kokai No. 10-287622, Kokai No. 2003-89687, Kokai No. 2004-203793, European Patent Publication No. 0563798, the International Patent Publication WO 95/32190 brochure, the International Patent Publication WO 03/000684 brochure), but they have not been clinically applied, and further development of useful compounds are being sought after.
Kokai (Japanese Unexamined Patent Publication) No. 60-89421 describes a compound represented by the following general formula (II) as a beta-adrenalin receptor antagonist:

wherein, R1 represents an isopropyl group or a t-butyl group, R2 represents a hydrogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group, a hydroxy group or an amino group, and R3 represents a hydrogen atom or a methyl group. The above compound has a structural similarity with the compound of the present invention in terms of being a phenylpyridazine derivative. However, it differs greatly in that it has a substituent at position 2 of the phenyl group whereas the compound of the present invention is characterized by being a pyridazinone derivative having as a substituent a phenyl group that has an alkoxy group at positions 3 and 4. Furthermore, it is neither mentioned nor known that these derivatives (II) have an inhibitory activity of PAI-1 production. Kokai (Japanese Unexamined Patent Publication) No. 10-59950 describes that a compound having the following general formula (III):

[wherein, R1 represents a C1-C4 alkyl group, a C3-C7 cycloalkyl group or the like, R2 represents a C1-C4 alkyl group, R3 represents a hydrogen atom, an optionally substituted C1-C5 alkyl group, C3-C7 cycloalkyl group or the like, and R4 and R5 represent a hydrogen atom, a C1-C6 alkyl group or the like, and the dotted line represents a single or double bond] has a potent PDE IV inhibiting activity, and bronchodilating and antiinflammatory activities. The above derivative (III) has a structural similarity with the compound of the present invention in terms of being a 5-dialkoxyphenyl-3-pyridazinone, but it differs greatly in that the bond between positions 4 and 5 of the pyridazinone ring is a single bond. Also, it is neither mentioned nor known that the above derivative (III) has an activity of inhibiting PAI-1 production. International Patent Publication WO 05/077953 describes a compound represented by the following general formula (IV):
The above derivative (IV) has a structural similarity with the compound of the present invention in terms of being a 5-phenyl-3-pyridazinone, but it differs greatly in that it has no alkoxy group at position 3 of the benzene ring or it is not a 5-dialkoxyphenyl-3-pyridazinone. Also, it is neither mentioned nor known that the above derivative (IV) has an activity of inhibiting PAI-1 production. International Patent Publication WO 05/121104 describes that a compound represented by the following general formula (V):
has an efficacy of combating plant diseases. The above derivative (IV) differs greatly with the compound of the present invention in that it has two phenyl groups on the pyridazinone ring. Also, it is neither mentioned nor known that the above derivative (V) has an activity of inhibiting PAI-1 production.